2-arylureidobenzoic acids: selective noncompetitive antagonists for the homomeric kainate receptor subtype GluR5

TY - JOUR

T1 - 2-arylureidobenzoic acids

T2 - selective noncompetitive antagonists for the homomeric kainate receptor subtype GluR5

AU - Valgeirsson, Jon

AU - Nielsen, Elsebet Ø

AU - Peters, Dan

AU - Varming, Thomas

AU - Mathiesen, Claus

AU - Kristensen, Anders S

AU - Madsen, Ulf

PY - 2003/12/18

Y1 - 2003/12/18

N2 - A series of 2-arylureidobenzoic acids (AUBAs) was prepared by a short and effective synthesis, and the pharmacological activity at glutamate receptors was evaluated in vitro and in vivo. The compounds showed noncompetitive antagonistic activity at the kainate receptor subtype GluR5. The most potent compounds showed more than 50-fold selectivity for GluR5 compared to GluR6 and the AMPA receptor subtypes GluR1-4. The structure-activity relationships for the AUBAs showed distinct structural requirements for the substituents on the two aromatic ring systems. Only para-substituents were tolerated on the benzoic acid moiety (ring A), whereas ring B tolerated a variety of substituents, but with a preference for lipophilic substituents. The most potent compounds had a 4-chloro substituent on ring A and 3-chlorobenzene (6b), 2-naphthalene (8h), or 2-indole (8k) as ring B and had IC(50) values of 1.3, 1.2, and 1.2 microM, respectively, in a functional GluR5 assay. Compound 6c (IC(50) = 4.8 microM at GluR5) showed activity in the in vivo ATPA rigidity test, indicating that 6c has better pharmacokinetic properties than 8h, which was inactive in this test. The AUBAs are the first example of a series of noncompetitive GluR5-selective antagonists and may prove to be important pharmacological tools and leads in the search for therapeutic glutamatergic agents.

AB - A series of 2-arylureidobenzoic acids (AUBAs) was prepared by a short and effective synthesis, and the pharmacological activity at glutamate receptors was evaluated in vitro and in vivo. The compounds showed noncompetitive antagonistic activity at the kainate receptor subtype GluR5. The most potent compounds showed more than 50-fold selectivity for GluR5 compared to GluR6 and the AMPA receptor subtypes GluR1-4. The structure-activity relationships for the AUBAs showed distinct structural requirements for the substituents on the two aromatic ring systems. Only para-substituents were tolerated on the benzoic acid moiety (ring A), whereas ring B tolerated a variety of substituents, but with a preference for lipophilic substituents. The most potent compounds had a 4-chloro substituent on ring A and 3-chlorobenzene (6b), 2-naphthalene (8h), or 2-indole (8k) as ring B and had IC(50) values of 1.3, 1.2, and 1.2 microM, respectively, in a functional GluR5 assay. Compound 6c (IC(50) = 4.8 microM at GluR5) showed activity in the in vivo ATPA rigidity test, indicating that 6c has better pharmacokinetic properties than 8h, which was inactive in this test. The AUBAs are the first example of a series of noncompetitive GluR5-selective antagonists and may prove to be important pharmacological tools and leads in the search for therapeutic glutamatergic agents.

KW - Animals

KW - Benzoates

KW - Cell Line

KW - Excitatory Amino Acid Agonists

KW - Humans

KW - Isoxazoles

KW - Mice

KW - Muscle Rigidity

KW - Patch-Clamp Techniques

KW - Propionates

KW - Quantitative Structure-Activity Relationship

KW - Radioligand Assay

KW - Receptors, Kainic Acid

KW - Urea

U2 - 10.1021/jm030428j

DO - 10.1021/jm030428j

M3 - Journal article

C2 - 14667236

SN - 0022-2623

VL - 46

SP - 5834

EP - 5843

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 26

ER -